Published in the journal Pediatrics, the study included 2,400 from 6 months old to 5 years old in Rochester, Nashville and Cincinnati in 2003-2004 and 2004-2005.
Nasal and throat swabs were used to determine whether children who came to the hospital or participating outpatient practice had the flu.
The researchers found that, even though those years had poor matches between the vaccine and the circulating flu strains, the shots were clearly protective during the 2004-05 year and possibly even during the 2003-04 year.
"These years were poor matches and fully vaccinated children were still half as likely to get the flu," said Katherine Eisenberg, B.A., an M.D., Ph.D. candidate at the University of Rochester School of Medicine and Dentistry and author of the paper published this month.
"Conservatively, we can estimate that vaccination for flu could prevent 2,250 hospitalizations and between 270,000 and 650,000 doctor visits for children if half of U.S. children 6 months to 5 years old were vaccinated," Katherine added.
The study showed that in the 2004-2005 flu seasons, the vaccine was effective almost 60 percent of the time in children between 6 months and 5 years old who were fully vaccinated compared to those who were not.
Partial vaccination - receiving one shot when two are recommended - did not provide any protection, suggesting that it was important that children received full vaccination.
Eisenberg said receiving only partial vaccination did not appear to protect children from flu.
Only 6 percent of the children in the study were fully vaccinated in 2003-2004, and 19 percent were fully vaccinated in 2004-2005. The 2006-2007 season was the first year the CDC recommended children up to 5 receive the vaccine.
The CDC now recommends children up to 18 years old receive the vaccine.
"It is incredibly important for all children to receive flu vaccinations for themselves and for the people around them," said Peter Szilagyi, M.D., M.P.H., a professor of Pediatrics and Community and Preventive Medicine at the University of Rochester Medical Center and an author of the paper.
"Children are notorious for unintentionally spreading illnesses. If we can prevent them from getting sick in the first place, we can prevent their loved ones from getting sick, especially younger siblings under 6 months who can't receive the vaccine and older grandparents who are at increased risk of complications from the flu," Szilagyi added.